tbuckley/cabot-search huggingface dataset:
Prevention of radiation-induced rectal injuries with perirectal blocks in radiation therapy.
Authors: Olga G. Rodionova, Pavel G. Sakun, Elena A. Sheiko, Elena A. Karnaukhova, Alla V. Pustovalova, Tatiana G. Chalabova, Dmitriy A. Savchenko, Sergey N. Kabanov, Meri L. Adamyan, Polina A. Kruze, Yuriy A. Poryvaev, Natalia V. Chernikova, Vitaliy I. Voshedskiy, Ekaterina A. Tolmacheva, Ekaterina O. Vasilieva, Anna A. Solntseva, Oksana E. Zhenilo, Anna A. Cherkasova, Yulia N. Krokhmal
Journal: Journal of Clinical Oncology (2022)

e17507 Background: The purpose of this study was to evaluate perirectal blocks in prevention of radiation-induced rectal injuries in patients with cervical cancer. Methods: The study included 18 patients diagnosed with stage III cervical cancer (T3bNxM0) receiving chemoradiotherapy. All patients showed pronounced inflammatory and dystrophic changes in tissue planes and organs of the small pelvis due to comorbidities (diabetes mellitus, hypertension, pelvic varicose veins, proctitis, inflammatory and adhesive processes in the small pelvis reducing chemoradiotherapy effectiveness due to impaired microcirculation and increasing the risk of post-radiation complications). All patients received brachytherapy with additional perirectal administration of drugs relieving pain and inflammation and improving neurotrophic processes and microcirculation in tissues (novocaine 0.25% -20.0; milgamma 2.0; ceftriaxone 1 g; dexamethasone 8 mg). The combined administration causes drug potentiation, positively affects the nervous and neuromuscular systems, restores microcirculation and venous outflow, decreases swelling, improves tissue trophism, reduces blood vessel permeability, and improves reflexes from interoceptors. Radiation therapy was completed on schedule with the introduction of radical doses in all patients, which is challenging in patients with comorbidities leading to impaired trophism and tissue hypoxia. Results: Complete tumor regression confirmed by MRI and ultrasound was observed by the end of the treatment in 90% of patients, apparently due to the radiosensitizing effect on cervical cancer and the radioprotective effect on surrounding tissues. Conclusions: Parametrial blocks during brachytherapy improve the status of tissues of the small pelvis which, in turn, prevents radiation damage, contributes to the timely radiotherapy completion, and improves the treatment effectiveness and the quality of life of patients. This technique is especially relevant in view of the increasing number of diseases that disrupt microcirculation, and hence the oxygenation of tissues, causing tumor radio- and chemoresistance.
Durvalumab (D) +/- tremelimumab (T) + chemotherapy (CT) in first-line (1L) metastatic (m) NSCLC: AE management in POSEIDON.
Authors: Byoung Chul Cho, Niels Reinmuth, Alexander Luft, Jorge Alatorre-Alexander, Sarayut Lucien Geater, Dmytro Trukhin, Sang-We Kim, Grygorii Ursol, Maen A. Hussein, Farah Louise Lim, Cheng-Ta Yang, Luiz H. Araujo, Haruhiro Saito, Miriam Marotti, Karen Barrett, Xiaojin Shi, Solange Peters, Edward B. Garon, Tony S. K. Mok, Melissa Lynne Johnson
Journal: Journal of Clinical Oncology (2022)

9035 Background: In the Phase 3 POSEIDON study in 1L mNSCLC, adding T to D+CT resulted in statistically significant improvements in PFS and OS vs CT. No new safety signals were identified and treatment discontinuations due to treatment-related AEs (TRAEs) were similar for the T+D+CT and D+CT arms (15.5% and 14.1%). Here we present details of AEs and their management. Methods: 1013 pts with EGFR/ ALK wild-type mNSCLC were randomized 1:1:1 to 1L T+D+CT, D+CT or CT. Safety was assessed in all treated pts. Results: 330, 334 and 333 pts received T+D+CT, D+CT and CT; 78%, 82% and 74% received at least 4 cycles of platinum-based CT. The most common grade 3/4 TRAEs were hematologic (anemia in 17%, 15% and 20% of pts in the T+D+CT, D+CT and CT arms and neutropenia in 16%, 13% and 12%) and most were managed using standard approaches per local practice; 22%, 18% and 16% of pts received colony stimulating factors and 22%, 21% and 26% received blood transfusions. All grade immune-mediated AEs (imAEs) occurred in 34%, 19% and 5% of pts in the T+D+CT, D+CT and CT arms; a higher incidence of diarrhea/colitis, dermatitis/rash and endocrinopathies was seen with the addition of T to D+CT (Table). Grade 3/4 imAEs occurred in 10%, 7% and 2% of pts in the T+D+CT, D+CT and CT arms, and serious imAEs in 10%, 6% and 1%; imAEs led to discontinuation of any study treatment in 6%, 4% and 0.6%, and led to death in 0.6%, 0.3% and 0%. Most imAEs were low grade and manageable with systemic corticosteroids (received by 26%, 13% and 4% of pts in the T+D+CT, D+CT and CT arms) or endocrine therapy (12%, 8% and 1%). Median time from first dose to onset of imAEs (TTO) was generally &gt; 60 days and the majority of non-endocrine imAEs resolved (Table). Conclusions: In POSEIDON, the safety profile of all regimens was manageable per standard guidelines and in line with the known profiles of D, T+D and CT; the most common grade 3/4 TRAEs were those typically associated with CT. As expected, more imAEs occurred with T+D+CT than D+CT, but the incidence of grade 3 or 4 imAEs, imAE-related deaths and treatment discontinuations due to imAEs was generally similar in the IO arms. T+D did not compromise the ability to administer planned CT. Clinical trial information: NCT03164616. [Table: see text]
RARE-16. Differential expression of miRNAs in adamantinomatous craniopharynngioma reveals dysregulation of pathogenic pathways
Authors: John Apps
Journal: Neuro-Oncology (2022)

Abstract MicroRNAs (miRNAs) are small non-coding RNAs that regulate the expression of target mRNAs and can control whole gene networks. ACPs are benign pituitary tumours that can result in significant morbidity and premature mortality. ACPs harbour mutations in CTNNB1 and are driven by the activation of the WNT/beta-catenin pathway. We sought to explore the expression of miRNAS in adamantinomatous craniopharyngioma (ACP) in a cohort of samples previously subjected to RNA-Seq analysis (Apps et al, Acta Neuropathologica, 2018, May;135(5):757-777). Total RNA ACP samples (n=18), non-functioning pituitary adenomas (n=3) and normal foetal pituitaries (n=3) underwent miRNA sequencing using the Qiagen miRNA library prep kit on a NextSeq 500 to a depth of 16 million reads. Differential expression was performed using DESeq2 and functional analysis with mirPath v.3. Expression of miRNAs was correlated with previously published mRNA expression We found that 210 miRNA were upregulated and 275 down regulated in ACP compared with controls (adjusted p-value &amp;lt;0.1). MIR-205-5p was the most upregulated miRNA (619 fold) and its expression correlated with genes expressed within the tumour epithelium (e.g. TP63). miR-375 an inhibitor of the WNT pathway was the most down regulated miRNA (361 fold). KEGG Pathway analysis identified Glycosphingolipid synthesis as the most enriched pathway targeted by upregulated miRNAs. Pathways that were enriched by down regulated miRNAs included: ECM-receptor interaction, fatty acid biosynthesis, Hippo, TGF-beta, WNT, and ErbB pathways. Down regulation of miR-132 has previously been suggested as a marker of aggressiveness in ACP, and was 16 fold down regulated (adjusted p-value&amp;lt;0.001) in this cohort and expression was inversely correlated with genes relating to epithelial development. This data confirms previous studies indicating that miRNA expression is altered in ACP. In silico analysis suggest that the dysregulation of miRNA affects the expression of genes involved in pathogenic pathways in ACP.
Actionable insights for managing inter-reader variability of RECIST overall response in lung clinical trials: A retrospective analysis.
Authors: Hubert Beaumont, Antoine Iannessi
Journal: Journal of Clinical Oncology (2022)

e21102 Background: To assess drug efficacy in clinical trials with imaging endpoints, the FDA recommends blinded independent central review (BICR) with double reads to ensure robust image interpretation. However, discordance created by double-reading adds burden and costs that stakeholders strive to minimize. Given that selection of tumors at baseline is reported to cause one third of adjudications, we tested a set of risk factors arising from baseline evaluations and trained models likely to predict discrepancies in RECIST responses. Methods: We pooled and retrospectively analyzed data from five lung cancer clinical trials that used RECIST with BICR and double reads including a total of 1720 patients. Firstly, we analyzed the distribution of four kinds of response discrepancies (KoD): progression or date of progression (PD), response or date of response (OR), progression or response (ANY) and best response (BR). We derived discrepancy rates, average time-point of the first occurrence of KoD and the proportion of time-points before KoD out of total time-point number (compared using Marascuilo procedure) as key indicators of the at-risk period of discordance. Secondly, from the baseline evaluations performed by readers, we computed the odds ratios of 32 risk factors for discrepancies including differences in measurements, tumor selection and disease locations. Finally, based on 77 features, we trained a Random Forest (RF) and a deep learning (DL) model to predict KoDs. Results: On average, respectively for PD, OR, ANY and BR, discrepancy rates were 41.5%, 49.1%, 66.3% and 28.7%; number of time-points for first occurrence were 4.6, 2.7, 2.7 and 4.8; and the proportion of time-points before KoD were 30.7%, 24.7%, 33.1% and 23.2% (significantly different). The main risk factors for discrepancies were miss-detection of measurable disease, completely different disease selection, miss-selection of lung tumors and when readers’ difference in sum of diameters was between 10% and 20%. However, associations were weak, with no association when one of the readers selected infrequent diseases (e.g., skin, gastric). DL outperformed RF. Classification performances were generally poor. PD was not predictable. BR performances were positive predictive value: 81.0 [95% CI: 78.8; 83.2], negative predictive value: 73.3 [95% CI: 72.8; 73.8]. Conclusions: The KoDs have different distributions, but all occur in the first third of the patient evaluation defining a risk period. We confirmed the reported association of selection and measurement at baseline with responses' variabilities. However, the associations were weak and did not allow good prediction of the variability in responses. For BICR of lung cancer trials using RECIST, our results support the implementation of a monitoring of variability focusing on the baseline and the beginning of the evaluation of the patients.
DIPG-22. Modifying the tumor microenvironment with a TIM-3 monoclonal antibody as a therapeutic strategy for DIPGs
Authors: Iker Ausejo-Mauleon, Sara Labiano, Daniel De la Nava, Marc Garcia-Moure, Virginia Laspidea, Oren J Becher, Li Jiang, Mariella G Filbin, Fernando Pastor, Marta M Alonso
Journal: Neuro-Oncology (2022)

Abstract Diffuse Midline Glioma, encompassing Diffuse Intrinsic Pontine Gliomas (DIPGs), are the most aggressive pediatric brain tumors. Their meager survival has not changed despite the combination of radiotherapy with targeted therapies emphasizing the urgent need for effective treatments. TIM-3 (HAVCR2) is a member of the T-cell immunoglobulin and mucin domain protein family. It is expressed on multiple immune cell types, including T cells, NK cells, myeloid populations, and microglia, regulating adaptive and innate immunity. In silico assessment of TIM-3 expression in DIPG datasets showed a robust expression of this gene. Single-cell sequencing analyses of DIPG biopsies uncover TIM-3 expression, especially in microglia. In vivo efficacy studies showed that treatment with AbTIM-3 significantly increased overall survival in two DIPG immunocompetent orthotopic models, led to long-term survivors (50%), and showed immune memory. TIM-3 treatment led to a significant increase in the tumor microenvironment of microglia, granulocytes, NK, and CD8+ cells and higher levels of IFNγ, GrzB and TNFα corresponding with an NK and T-cell activate phenotypes. Interestingly, there was a decrease in the Treg population which causes an increase in the pro-inflammatory CD8/Treg ratio. CD4, CD8 or NK cell depletion leads to a significant but not a total loss of treatment efficacy. CD4+ and CD8+ cells were aumented in treated draining lymph nodes and expressed higher amounts of pro-inflamattory cytokines than control-mice. Population analysis and depletion experiments demonstrated the relevance of NK, CD4, CD8 and myeloid populations in the response to anti-TIM-3 therapy. Interestingly, the depletion of the different immune populations combined or using immunodeficient Rag2 mice, did not completely abrogate the treatment efficacy. These results suggest the concurrence of an additional mechanism of action that together with the immune response leads to a robust anti-DIPG effect. In conclusion, these data demonstrate that TIM-3 is a potential target for the treatment of DIPG.
LGG-27. Molecular implications of mitogen-activated protein kinase pathway inhibition by the MEK inhibitor trametinib in BRAF-fusion-driven pediatric pilocytic astrocytoma
Authors: Romain Sigaud, Anja Stefanski, Florian Selt, Thomas Hielscher, Diren Usta, Daniela Kocher, Daniel Picard, Isabel Büdenbender, Marc Remke, Stefan M Pfister, David T W Jones, Tilman Brummer, Olaf Witt, Till Milde
Journal: Neuro-Oncology (2022)

Abstract Pilocytic astrocytomas (PA) are the most common pediatric brain tumors. They are characterized by driving alterations in the mitogen-activated protein kinase (MAPK) pathway, leading to its constitutive activation and modulating the balance between cell proliferation and oncogene-induced senescence (OIS) sustained by senescence-associated secretory phenotype (SASP) factors. This makes PA susceptible to MAPK inhibitor (MAPKi) therapies, which show encouraging results in phase 1/2 clinical trials. However, little is known about the molecular implications of MAPK inhibition in PA. The DKFZ-BT66 cell line, derived from a primary KIAA:BRAF-fusion positive PA, was used as a model system. DKFZ-BT66 were treated with the MEKi trametinib for different durations in both proliferative and senescent states. Gene expression was analyzed by gene expression profiling and protein expression/phospho-regulation by data-dependent mass spectrometry followed by label-free quantitative analysis. A time course analysis based on differentially expressed genes and phosphorylated proteins was performed, followed by a single-sample gene set enrichment analysis (ssGSEA) and kinase substrate enrichment analysis, respectively. Differential gene expression analysis revealed that MEK inhibition led to the inhibition of the OIS/SASP gene programs in senescent DKFZ-BT66, with downregulation of key OIS/SASP partners such as IL1B on the protein level. This functionally translated into a de-sensitization of these cells towards the senolytic agent navitoclax. ssGSEA showed that most MAPK-related signatures were downregulated upon MEKi treatment, while pathways related to upstream MAPK activators (including FGFR, NTRK and TGFB pathways) were upregulated, in both proliferating and senescent DKFZ-BT66. This data indicates that MAPKi reverses OIS in senescent PA cells, while inducing the activation of MAPK upstream regulators in proliferating and senescent PA cells, identifying putative co-targets that could help increase treatment’s efficacy. Validation of these targets by post-translational modification enrichment analysis of the phospho-proteomics dataset is ongoing.
Lactate dehydrogenase as a surrogate marker for both PCR and survival in breast cancer patients who underwent neoadjuvant chemotherapy.
Authors: In Hee Lee, Yee Soo Chae, Jeeyeon Lee, Ho Yong Park, Jin Hyang Jung, Ji-young Park, Jee-Young Park
Journal: Journal of Clinical Oncology (2022)

e12621 Background: Glucose metabolism in cancer cells produces various glycolytic metabolites, which can affect cancer progression and treatment outcome. Herein we evaluated the association of glucose transporters and enzymes involved in glucose metabolism with clinic-pathological factors and outcomes in breast cancer patients who underwent neoadjuvant chemotherapy(NAC). Methods: We selected 7 target transporters and enzymes(GLUT1, hexokinase 2, lactate dehydrogenase, MCT1, MCT4, IGF1RA, and IGF1RB) involved in glucose metabolism. Their tumoral expressions were scored both quantitively and qualitatively based on tissue microarrays and immunohistochemistry as previously described (Pinheiro et al, 2010) and then evaluated in relationships with pretreatment clinical/pathological characteristics and treatment outcomes including findings of 18F-FDG PET/CT,pathologic complete response(pCR), and relapse in breast cancer(stage IIA-IIIC) patients who underwent anthracycline or taxane-based NAC. Results: Of the 236 enrolled patients, 145(61.4%), 44(18.6%), and 47(19.9%) were luminal, HER2-enriched, and TNBC subtypes. Pathologic CR was determined 50(21.2%) and 57(24.2%) relapses, 42(17.8%) distant relapses, and 28 deaths were observed during median follow-up duration of 64.0 (32.3-114.9) months. The expression rates of the target molecules were 76.0, 31.1, 42.1, 54.9, 67.9, 78.4, and 49.8% for GLUT1, hexokinase 2 (HK2), lactate dehydrogenase(LD), MCT1, MCT4, IGF1RA, and IGF1RB, respectively. Among target molecules in glucose metabolism, LD was significantly associated with pCR(OR = 0.251; p- = 0.016) and distant disease-free survival (HR = 2.29; P = 0.019). Plus, LD expression shows a trend for a high SUVmax of primary tumor 18F-FDG PET/CT(OR = 1.797 P = 0.060). Conclusions: Tumoral expression of lactate dehydrogenase can be considered as a predictive marker for pCR to NAC and plus prognostic marker for survival in patients with breast cancer.
Intranasal Delivery of Functionalized Polymeric Nanomaterials to the Brain (Adv. Healthcare Mater. 11/2022)
Authors: Shuai Zha, Ka‐Leung Wong, Angelo H. All
Journal: Advanced Healthcare Materials (2022)

Intranasal Delivery In article number 2102610, Angelo H. All and co-workers review the intranasal (IN) delivery of polymeric nanomaterials containing therapeutic agents to the brain and their current challenges and future perspectives. Functionalized polymeric nanomaterials move along the olfactory and trigeminal nerves, and it is expected that clinical translations of IN delivery will be comprehensively exploited.
Autophagy Is Impaired in Fetal Hypoplastic Lungs and Rescued by Administration of Amniotic Fluid Stem Cell Extracellular Vesicles
Authors: Kasra Khalaj, Lina Antounians, Rebeca Lopes Figueira, Martin Post, Augusto Zani
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Pulmonary hypoplasia secondary to congenital diaphragmatic hernia is characterized by reduced branching morphogenesis, which is responsible for poor clinical outcomes. Administration of amniotic fluid stem cell extracellular vesicles (AFSC-EVs) rescues branching morphogenesis in rodent fetal models of pulmonary hypoplasia. Herein, we hypothesized that AFSC-EVs exert their regenerative potential by affecting autophagy, a process required for normal lung development. Objectives: To evaluate autophagy in hypoplastic lungs throughout gestation and establish whether AFSC-EV administration improves branching morphogenesis through autophagy-mediated mechanisms. Methods: EVs were isolated from c-kit+ AFSC-conditioned medium by ultracentrifugation and characterized for size, morphology, and EV markers. Branching morphogenesis was inhibited in rat fetuses by nitrofen administration to dams and in human fetal lung explants by blocking RAC1 activity with NSC23766. The expression of autophagy activators (BECN1 and ATG5) and adaptor (SQSTM1/p62) was analyzed in vitro (rat and human fetal lung explants) and in vivo (rat fetal lungs). Mechanistic studies on rat fetal primary lung epithelial cells were conducted using inhibitors for microRNA-17 and -20a contained in the AFSC-EV cargo and known to regulate autophagy. Measurements and Main Results: Rat and human models of fetal pulmonary hypoplasia showed reduced autophagy mainly at pseudoglandular and canalicular stages. AFSC-EV administration restored autophagy in both pulmonary hypoplasia models by transferring miR-17∼92 cluster members contained in the EV cargo. Conclusions: AFSC-EV treatment rescues branching morphogenesis partly by restoring autophagy through microRNA cargo transfer. This study enhances our understanding of pulmonary hypoplasia pathogenesis and creates new opportunities for fetal therapeutic intervention in congenital diaphragmatic hernia babies.
Low doses of visible electromagnetic radiation activating endogenous nonspecific antitumor resistance in patients with cervical cancer.
Authors: Olga G. Rodionova, Pavel G. Sakun, Elena A. Sheiko, Elena A. Karnaukhova, Alla V. Pustovalova, Tatiana G. Chalabova, Dmitriy A. Savchenko, Sergey N. Kabanov, Meri L. Adamyan, Polina A. Kruze, Yuriy A. Poryvaev, Natalia V. Chernikova, Vitaliy I. Voshedskiy, Ekaterina A. Tolmacheva, Ekaterina O. Vasilieva, Anna A. Solntseva, Oksana E. Zhenilo, Anna A. Cherkasova, Julia N. Krokhmal
Journal: Journal of Clinical Oncology (2022)

e17506 Background: Ionizing radiation inhibits the immunological reactivity of the body and the system of nonspecific antitumor resistance in patients with cervical cancer (CC). The purpose of this study was to activate the system of nonspecific antitumor resistance using visible electromagnetic radiation in CC patients receiving chemoradiotherapy. Methods: The study included 30 patients, mean age 61 years, with stage IIIb CC (T 3b N x M 0 ). The main group (n = 15) received standard chemoradiotherapy (CRT): irradiation of the primary focus 80 Gy, lymphatic paths 55 Gy, with radiomodification with cisplatin 40mg/m2; the patients were additionally exposed to visible electromagnetic radiation: the red spectrum λ = 640 nm on the cubital vein projection (exposure time 5 minutes, dose 6.86 J/cm2), twice a week (the total of 14 sessions). The method is based on the ability of monochrome red light to induce photobioadaptive processes in the body, leading to the formation of non-specific antistress reactions, activation of reparative and regenerative tissue reactions with an increase in the synthetic, phagocytic activity of neutrophils and the growth of the immunity lymphoid indicators. The control group included 12 patients receiving only standard CRT. Parameters of nonspecific antitumor adaptation reactions were evaluated. Results: Lower abdominal pain and discomfort were managed in 20% of patients of the main group on day 8, in 30% on day 10, and in 50% on day 14. In the control group, the symptoms were managed in 40% of patients only on day 22. More rapid regression of the cervical tumor was registered in patients of the main group, as well as decreased infiltration of the parametrium and vaginal fornices, disappearance of bloody discharge, management of intoxication syndrome. Gastrointestinal toxicity (nausea, diarrhea, flatulence) was noted in 10% of patients in the main group and in 100% controls. 7 patients in the control group developed leukopenia; in the main group, it was not observed. MRI-confirmed complete tumor regression amounted to 88% in the main group and 65% in the control group. CRT was completed within 7 weeks in the main group and 8.5 weeks in the control group. Conclusions: Low doses of electromagnetic radiation of the red spectrum activate endogenous nonspecific antitumor resistance of the body by forming nonspecific antistress reactions of activation and increasing the immunity lymphoid indicators, which improves the efficacy of CRT.